Abstract
We compared a standard antihypertensive losartan treatment with a pharmacogenomics-guided rostafuroxin treatment in never-treated Caucasian and Chinese patients with primary hypertension. Rostafuroxin is a digitoxigenin derivative that selectively disrupts the binding to the cSrc-SH2 domain of mutant α-adducin and of the ouabain-activated Na-K pump at 10–11 M. Of 902 patients screened, 172 were enrolled in Italy and 107 in Taiwan. After stratification for country and genetic background, patients were randomized to rostafuroxin or losartan, being the difference in the fall in office systolic blood pressure (OSBP) after 2-month treatment the primary endpoint. Three pharmacogenomic profiles (P) were examined, considering: P1, adding to the gene variants included in the subsequent P2, the variants detected by post-hoc analysis of a previous trial; P2, variants of genes encoding enzymes for endogenous ouabain (EO) synthesis (LSS and HSD3B1), EO transport (MDR1/ABCB1), adducin (ADD1 and ADD3); P3, variants of the LSS gene only. In Caucasians, the group differences (rostafuroxin 50 μg minus losartan 50 mg in OSBP mmHg) were significant both in P2 adjusted for genetic heterogeneity (P2a) and P3 LSS rs2254524 AA [9.8 (0.6–19.0), P = 0.038 and 13.4 (25.4–2.5), P = 0.031, respectively]. In human H295R cells transfected with LSS A and LSS C variants, the EO production was greater in the former (P = 0.038); this difference was abolished by rostafuroxin at 10–11 M. Chinese patients had a similar drop in OSBP to Caucasians with losartan but no change in OSBP with rostafuroxin. These results show that genetics may guide drug treatment for primary hypertension in Caucasians.
Highlights
Rostafuroxin has been developed as a selective inhibitor of the ouabain blood pressure effects initially [1,2,3]
After having obtained data supporting a plausible role of adducin variants or of endogenous ouabain (EO) in triggering hypertension in a rodent model and in humans [1, 2, 6,7,8,9,10,11], we developed a strategy that takes into account the above mentioned four issues by, (1) applying the concept of genetic profile, in order to capture at least a portion of the genetic heterogeneity underlying adducin and EO functions [13]; (2) limiting the studies to newly discovered and never treated patients [13]; (3) assessing causation with rostafuroxin [4, 12]
Besides the fact that we aimed to compare a generic drug as losartan that is one of the mainly used in the treatment for hypertension, the rationale underlying the choice of naïve patients and the losartan as a comparator is explained in the onlineonly Supplementary Data
Summary
Rostafuroxin has been developed as a selective inhibitor of the ouabain blood pressure effects initially [1,2,3]. After having obtained data supporting a plausible role of adducin variants or of endogenous ouabain (EO) in triggering hypertension in a rodent model and in humans [1, 2, 6,7,8,9,10,11], we developed a strategy that takes into account the above mentioned four issues by, (1) applying the concept of genetic profile, in order to capture at least a portion of the genetic heterogeneity underlying adducin and EO functions [13]; (2) limiting the studies to newly discovered and never treated (naïve) patients [13]; (3) assessing causation with rostafuroxin [4, 12] By applying this strategy, we identified the genetic profile 2 (P2), associated with the rostafuroxin blood pressure response, within the phase 2a OASIS-HT trial (ouabain and adducin for specific intervention on sodium in hypertension trial) [13]. P2 consists of variants at α-adducin (ADD1 rs4961), γ-adducin (ADD3 rs3731566), lanosterol synthase (LSS rs2254524), 3β-hydroxysteroid dehydrogenase/δ(5)-δ(4)isomerase type 1 (HSD3B1 rs10923835), and ATP-binding cassette subfamily B member 1 (ABCB1/MDR1 rs1045642) genes, the last three being involved in the regulation of EO tissue levels
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
